EP1419158B1 - Pteridinone derivatives as modulators of chemokine receptor activity - Google Patents

Pteridinone derivatives as modulators of chemokine receptor activity Download PDF

Info

Publication number
EP1419158B1
EP1419158B1 EP02749129A EP02749129A EP1419158B1 EP 1419158 B1 EP1419158 B1 EP 1419158B1 EP 02749129 A EP02749129 A EP 02749129A EP 02749129 A EP02749129 A EP 02749129A EP 1419158 B1 EP1419158 B1 EP 1419158B1
Authority
EP
European Patent Office
Prior art keywords
amino
methyl
hydroxy
thio
difluorophenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP02749129A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP1419158A1 (en
Inventor
Roger Victor Bonnert
Peter Alan Cage
Simon Frazer Hunt
Iain Alastair Stewart Walters
Rupert Philip AstraZeneca R&D Chamwood AUSTIN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Publication of EP1419158A1 publication Critical patent/EP1419158A1/en
Application granted granted Critical
Publication of EP1419158B1 publication Critical patent/EP1419158B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to certain heterocyclic compounds, processes and intermediates used in their preparation, pharmaceutical compositions containing them and their use in therapy.
  • Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif. At the present time, the chemokine superfamily comprises three groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C), Cys-Cys (C-C)) and Cys-X 3 -Cys (C X 3 -C) families.
  • the C-X-C and C-C families have sequence similarity and are distinguished from one another on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues.
  • the C-X 3 -C family is distinguished from the other two families on the basis of having a triple amino acid insertion between the NH-proximal pair of cysteine residues.
  • the C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).
  • IL-8 interleukin-8
  • NAP-2 neutrophil-activating peptide 2
  • the C-C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils.
  • Examples include human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins 1 ⁇ and 1 ⁇ (MIP-1 ⁇ and MIP-1 ⁇ ).
  • the C-X 3 -C chemokine (also known as fractalkine) is a potent chemoattractant and activator of microglia in the central nervous system (CNS) as well as of monocytes, T cells, NK cells and mast cells.
  • chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX 3 CR1 for the C-X 3 -C family.
  • These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above.
  • WO-01/19825 discloses pteridinones as kinase inhibitors.
  • WO-02/32507 discloses 7-amino-2-alkylthiopteridin-4-yl-amines for the treatment of chemokine related disorders.
  • WO-01/62758 discloses pteridine compounds for the treatment of psoriasis.
  • WO-01/58906 discloses pyrimidine compounds as modulators of chemokine receptor activity.
  • WO-00/09511 and WO-01/25242 disclose thiazolopyrimidines.
  • the present invention therefore provides compounds of formula (I) and pharmaceutically acceptable salts, solvates or in vivo hydrolysable esters thereof: in which:
  • the present invention further provides compounds of formula (I) and pharmaceutically acceptable salts or solvates thereof: in which:
  • alkyl includes both straight-chain and branched-chain alkyl groups.
  • references to individual alkyl groups such as "propyl” are specific for the straight chain version only and references to individual branched-chain alkyl groups such as t-butyl are specific for the branched chain version only.
  • Examples of C 1- C 3 alkyl include methyl, ethyl, propyl.
  • Examples of C 1- C 6 alkyl include the examples of C 1 -C 3 alkyl and additionally butyl, t -butyl, pentyl, 2-methylbutyl and hexyl.
  • C 1 -C 8 alkyl examples include the examples of C 1 -C 6 alkyl and additionally heptyl, 2-ethyl-3-methylbutyl and octyl.
  • An analogous convention applies to other terms such as alkenyl and alkynyl.
  • C 2 -C 6 alkenyl includes vinyl, allyl, 1-propenyl, 2-butenyl, 2-methylbut-2-enyl, and 4-hexenyl.
  • Examples of C 2 -C 6 alkynyl include ethynyl, 1-propynyl, 2-propynyl and 1-methylpent-2-ynyl.
  • C 3 -C 7 carbocyclic is a saturated, partially saturated or unsaturated ring system containing 3 to 7 ring carbon atoms.
  • C 3 -C 7 carbocyclic groups include cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl.
  • Examples of 4- to 7-membered saturated heterocyclic ring systems optionally containing a further heteroatom selected from oxygen and nitrogen atoms include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl.
  • Aryl groups include phenyl and naphthyl.
  • Heteroaryl is defined as a 5- or 6-membered aromatic ring containing one or more heteroatoms selected from N, S, O. Examples include pyridine, pyrimidine, thiazole, oxazole, pyrazole, imidazole, furan. Further examples include pyridine, pyrimidine, thiazole, oxazole, pyrazole, imidazole, furan, triazole and thiadiazole.
  • Halogen atoms include fluorine, chlorine, bromine and iodine.
  • Preferred halogen atoms are fluorine and chlorine.
  • a group is substituted or optionally substituted by one or more substitutents it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.
  • one or more means 1, 2 or 3.
  • One or more may also mean 1 or 2.
  • a ring contains or optionally contains one or more atoms, preferably it contains 1, 2, 3 or 4 atoms.
  • Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.
  • the invention further encompasses all solvated forms of compounds of formula (I) and salts thereof.
  • R 1 , R 2 , R 3 and Y are as follows. Such values may be used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.
  • the group R 1 represents a C 3 -C 7 carbocyclic, C 1 -C 8 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl group, each of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, -OR 4 , -NR 5 R 6 , -CONR 5 R 6 , -COOR 7 , - NR 8 COR 9 , -SR 10 , -SO 2 R 10 , -SO 2 NR 5 R 6 , -NR 8 SO 2 R 9 , an aryl or heteroaryl group both of which can be optionally substituted by one or more substituents independently selected from halogen atoms, cyano, nitro, -OR 4 , -NR 5 R 6 , -CONR 5 R 6 , -COOR 7 , -NR 8 COR 10 , -SR 10 , -SO 2 R 10 , -SO 2 R 10
  • R 1 represents an optionally substituted benzyl group. More preferably R 1 represents benzyl or benzyl substituted by one or more C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or halogen atoms, in particular benzyl substituted by two halogen atoms.
  • R 2 and R 3 is hydrogen and the other is C 1 -C 8 alkyl substituted by hydroxy and one or more methyl or ethyl groups. More preferably one of R 2 and R 3 is hydrogen and the other is CH(CH 3 )CH 2 OH, CH(Et)CH 2 OH, C(CH 3 ) 2 CH 2 OH or CH(CH 2 OH) 2 . When one of R 2 and R 3 is hydrogen and the other is CH(CH 3 )CH 2 OH or CH(Et)CH 2 OH the resulting compounds of formula (I) are preferably in the form of the (R) isomer. Most preferably one of R 2 and R 3 is hydrogen and the other is CH(CH 3 )CH 2 OH.
  • Y represents -NR 20 R 21 , -OR 4 , -SR 4 , a heteroaryl group or -NR 5 R 6 where R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring system optionally containing a further heteroatom selected from oxygen and nitrogen atoms, which ring system may be optionally substituted by one or more substituent groups independently selected from -OH, -NH 2 or C 1 -C 4 alkyl.
  • R 20 and R 21 is hydrogen or methyl and the other is a C 3 -C 7 carbocyclic substituted by hydroxy or it is C 1 -C 4 alkyl substituted by -OR 4 , heteroaryl optionally substituted by methyl, or a 3-8 membered ring optionally containing one or more atoms selected from O, S and NR 8 .
  • R 4 represents hydrogen or a C 1 -C 6 alkyl group the latter of which may be optionally substituted by -NR 5 R 6 or an heteroaryl group which may be optionally substituted by one or more substituents independently selected from halogen atoms, cyano, nitro, -OR 11 , -NR 5 R 6 , - CONR 5 R 6 , -NR 8 COR 9 , -SO 2 NR 5 R 6 , -NR 8 SO 2 R 9 , C 1 -C 6 alkyl and trifluoromethyl groups; or R 4 represents a heteroaryl group which may be optionally substituted by one or more substituents independently selected from -OH and methyl.
  • R 5 and R 6 is hydrogen and the other is C 1 -C 6 alkyl or a heteroaryl group; or together with the nitrogen atom to which they are attached R 5 and R 6 form a 4- to 7-membered saturated heterocyclic ring system optionally containing a further heteroatom selected from oxygen and nitrogen atoms, which ring system may be optionally substituted by one or more substituent groups independently selected from -OH, -NH 2 or C 1 -C 4 alkyl.
  • a preferred class of compound is of formula (I) in which;
  • Another preferred class of compound is of formula (I) in which;
  • Another preferred class of compound is of formula (I) in which;
  • Particularly preferred compounds of the invention include:
  • reaction of compounds of formula (IIA) with an amine HNR 20 R 21 may be performed in a solvent such as N-methylpyrrolidinone at a temperature between 0°C and 150°C in the presence of a base such as N,N- diisopropylethylamine.
  • reaction of compounds of formula (IIA) with an alcohol R 4 OH may be performed using the alcohol R 4 OH as solvent at a temperature between 0°C and 150°C in the presence of a base such as butyllithium.
  • reaction of compounds of formula (IIA) with a thiol R 4 SH may be performed in a solvent such as DMSO at a temperature between 0°C and 150°C in the presence of a base such as potassium tert-butoxide.
  • reaction of compounds of formula (IIA) with an amine HNR 5 R 6 may be performed in a solvent such as N-methylpyrrolidinone at a temperature between 0°C and 150°C in the presence of a base such as N,N- diisopropylethylamine
  • reaction of compounds of formula (IIA) with a heteroarene may be performed in a solvent such as DMSO at a temperature between 0°C and 100°C in the presence of a base such as potassium tert-butoxide.
  • reaction of compounds of formula (IIB) with diethyl oxalate may be performed in the absence of solvent at a temperature between 50°C and 200°C.
  • reaction of compounds of formula (IIB) with iminomethoxy-acetic acid, methyl ester hydrochloride may be performed in ethanol in the presence of base such as N,N- diisopropylethylamine at a temperature between 0°C and 150°C.
  • Compounds of formula (IV) where R 1 is as defined in formula (I) may be prepared by treating a compound of formula (V) where R 1 is as defined above with a nitrosating agent such as sodium nitrite.
  • the reaction may be performed in a solvent such as aqueous acetic acid at a temperature between 0°C and 100°C.
  • Compounds of formula (V) where R 1 is as defined in formula (I) may be prepared by treating a compound of formula (VI) with a compound of formula R 1 X where R 1 is as defined above and X is a leaving group such as bromide in the presence of a base such as potassium tert-butoxide.
  • the reaction may be performed in a solvent such as DMSO at room temperature.
  • Novel intermediate compounds form a further aspect of the invention.
  • L is a leaving group selected from hydroxy, bromo or chloro;
  • R 2 is hydrogen;
  • R 3 is CH(CH 3 )CH 2 OH; and
  • R 1 is benzyl substituted by two fluorine atoms.
  • the compounds of formula (I) above may be converted to a pharmaceutically acceptable salt or solvate thereof, preferably a basic addition salt such as sodium, potassium, calcium, aluminium, lithium, magnesium, zinc, henzathine, chloroprocaine, choline, diethanolamine, ethanolamine, ethyldiamine, meglume, tromethamine or procaine, or an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate.
  • a basic addition salt such as sodium, potassium, calcium, aluminium, lithium, magnesium, zinc, henzathine, chloroprocaine, choline, diethanolamine, ethanolamine, ethyldiamine, meglume, tromethamine or procaine
  • an acid addition salt such as a hydrochloride, hydrobromide, phosphat
  • the compounds of formula (I) above may be converted to a pharmaceutically acceptable in vivo hydrolysable ester thereof.
  • An in vivo hydrolysable ester of a compound of formula (I) that contains a carboxy or a hydroxy group is, for example a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • esters can be identified by administering, for example, intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluid.
  • Suitable pharmaceutically acceptable esters for carboxy include C 1 -C 6 alkoxymethyl esters for example methoxymethyl, C 1 -C 6 alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C 3 -C 8 cycloalkoxycarbonyloxyC 1 -C 6 alkyl esters for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters for example 5-methyl-1,3-dioxolen-2-onylmethyl; and C 1 -C 6 alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.
  • Suitable pharmaceutically-acceptable esters for hydroxy include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in-vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s.
  • inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in-vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s.
  • ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy.
  • a selection of in-vivo hydrolysable ester forming groups for hydroxy include C 1 -C 10 alkanoyl, for example formyl, acetyl; benzoyl; phenylacetyl; substituted benzoyl and phenylacetyl, C 1 -C 10 alkoxycarbonyl (to give alkyl carbonate esters), for example ethoxycarbonyl; di-(C 1 -C 4 )alkylcarbamoyl and N -(di-(C 1 -C 4 )alkylaminoethyl)- N- (C 1 -C 4 )alkylcarbamoyl (to give carbamates); di-(C 1 -C 4 )alkylaminoacetyl and carboxyacetyl.
  • C 1 -C 10 alkanoyl for example formyl, acetyl; benzoyl; phenylacetyl; substituted benzoyl and
  • ring substituents on phenylacetyl and benzoyl include aminomethyl, (C 1 -C 4 )allcylaminomethyl and di-((C 1 -C 4 )alkyl)aminomethyl, and morpholino or piperazino linked from a ring nitrogen atom via a methylene linking group to the 3- or 4- position of the benzoyl ring.
  • Other interesting in-vivo hydrolysable esters include, for example, R A C(O)O(C 1 -C 6 )alkyl-CO-, wherein R A is for example, benzyloxy-(C 1 -C 4 )alkyl, or phenyl).
  • Suitable substituents on a phenyl group in such esters include, for example, 4-(C 1 -C 4 )piperazino-(C 1 -C 4 )alkyl, piperazino-(C 1 -C 4 )alkyl and morpholino-(C 1 -C 4 )alkyl.
  • the compounds of formula (I) have activity as pharmaceuticals, in particular as modulators of chemokine receptor (especially CXCR2) activity, and may be used in the treatment (therapeutic or prophylactic) of conditions/diseases in human and non-human animals which are exacerbated or caused by excessive or unregulated production of chemokines.
  • modulators of chemokine receptor especially CXCR2
  • CXCR2 chemokine receptor 2
  • Examples of such conditions/diseases include:
  • the present invention provides a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
  • the present invention also provides a pharmaceutically acceptable in vivo hydrolysable ester of a compound of formula (I), as hereinbefore defined for use in therapy.
  • the compounds of the invention are used to treat diseases in which the chemokine receptor belongs to the CXC chemokine receptor subfamily, more preferably the target chemokine receptor is the CXCR2 receptor.
  • Particular conditions which can be treated with the compounds of the invention are psorisis, rheumatoid arthritis, diseases in which angiogenesis is associated with raised CXCR2 chemokine levels, and respiratory disease such as COPD. It is preferred that the compounds of the invention are used to treat rheumatoid arthritis. The compounds of the invention may also be used to treat COPD.
  • certain compounds of formula (I) may have utility as antagonists of the CX3CR1 receptor.
  • Such compounds are expected to be particularly useful in the treatment of disorders within the central and peripheral nervous system and other conditions characterized by an activation of microglia and/or infiltration of leukocytes (e.g. stroke/ischemia and head trauma).
  • the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined as a medicament.
  • the present invention provides the use of a pharmaceutically acceptable in vivo hydrolysable ester of a compound of formula (I), as hereinbefore defined as a medicament.
  • the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
  • the present invention also provides the use of a pharmaceutically acceptable in vivo hydrolysable ester of a compound of formula (I), as hereinbefore defined in the manufacture of a medicament for use in therapy.
  • the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for the treatment of human diseases or conditions in which modulation of chemokine receptor activity is beneficial.
  • the present invention also provides the use of a pharmaceutically acceptable in vivo hydrolysable ester of a compound of formula (I), as hereinbefore defined in the manufacture of a medicament for the treatment of human diseases or conditions in which modulation of chemokine receptor activity is beneficial.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be construed accordingly.
  • chemokine binds to a chemokine (especially CXCR2) receptor, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
  • chemokine binds to a chemokine (especially CXCR2) receptor, which comprises administering to a patient a therapeutically effective amount of a pharmaceutically acceptable in vivo hydrolysable ester of a compound of formula (I), as hereinbefore defined.
  • a method of treating an inflammatory disease especially rheumatoid arthritis, COPD and psoriasis, in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof, as hereinbefore defined.
  • a compound of formula (I) or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof, as hereinbefore defined.
  • the method of treating rheumatoid arthritis is provided.
  • a method of treating COPD is also provided.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable in vivo hydrolysable ester of a compound of formula (I), as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a pharmaceutically acceptable in vivo hydrolysable ester of a compound of formula (I), as hereinbefore defined, with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • compositions may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally.
  • the compounds of the invention are administered orally.
  • High pressure liquid chromatography purification was performed using a Waters Micromass LCZ with a Waters 600 pump controller, Waters 2487 detector and Gilson FC024 fraction collector or a Waters Delta Prep 4000 or a Gilson Auto-Purification System.
  • the abbreviations m.p. and DMSO used in the examples stand for melting point and dimethyl sulphoxide respectively.
  • step (a) The product of Example 1, step (a) (2.5g) was dissolved in acetic acid (150ml) and the solution cooled to 5°C. A solution of sodium nitrite (625mg) in water (50ml) was added dropwise resulting in a dark blue colouration. The reaction was stirred at room temperature for 30 minutes during which time a pink solid precipitated from solution.
  • step (c) The product of Example 1, step (c) (0.5g) was suspended in DMSO (10ml) and bromoform (10ml) and the mixture was heated to 125°C. Isoamylnitrite (2ml) was added and the mixture was stirred at 125°C for 5 minutes before being cooled in an ice bath. Solvent was removed by evaporation under high vacuum and the residue suspended in dichloromethane (100ml). This suspension was washed with saturated aqueous ammonium chloride (50ml) and then filtered through a plug of celite.
  • step (d) The product of Example 1, step (d) (8.7g) was dissolved in N-methylpyrrolidinone (40ml) and Hunigs base (7.9ml) was added followed by D-alaninol (2.7ml). The mixture was stirred at 100°C for 15mins. The cooled solution was poured onto water, (11), and acidified with dilute hydrochloric acid. The solid which separated was collected, washed with water and air dried. Crystallisation from acetonitrile afforded the title compound as a pale yellow solid (7.4g). m.p.
  • step (e) The product of Example 1, step (e) (5.0g) was suspended in acetonitrile (200ml) and bromine (1.2ml) added. The reaction was stirred at room temperature for 2 hours, then evaporated to dryness. The crude product was purified by column chromatography on silica gel, eluting with 2% methanol in dichloromethane to give the subtitled compound as a pale yellow solid (1.7g).
  • step (f) 50mg
  • benzylamine (35mg) and N,N- diisopropylethylamine (38ul) were dissolved in N-methylpyrrolidinone (2ml) and heated to 100°C for 2 hours.
  • the cooled reaction mixture was diluted with ethyl acetate and washed 5x with saturated aqueous ammonium chloride.
  • the organic phase was dried over magnesium sulphate, filtered and evaporated.
  • the crude product was purified by column chromatography on silica gel, eluting with 2% methanol in dichloromethane to give the titled compound as a pale yellow solid (24mg). m.p.
  • step (a) (73g) was added to a solution of 2-picoline (40ml) in POCl 3 (300ml) and the mixture refluxed for 24hr.
  • the reaction mixture was concentrated in vacuo to half its original volume and poured onto ice and then neutralized with ammonia, forming a brown solid. This mixture was refluxed for 1hr, and the precipitate isolated by filtration, washing with water.
  • the crude product was purified by silica gel chromatography, eluting with dichloromethane to afford the subtitled compound as a white solid (31.7g).
  • step (c) 22g in acetic acid (300ml) at room temperature was added a solution of sodium nitrite (4.8g) in water (30ml). The reaction was stirred at 0°C for 30min, and the resultant purple precipitate isolated by filtration, washing with water, to give the subtitled compound as a dark blue solid (37g, not completely dry).
  • step (d) To a solution of acetic acid (10ml) in boiling ethanol (300ml) was added zinc dust (15g) and the product of Example 3, step (d) (10g). The reaction was heated at reflux for 10 mins, cooled, filtered through celite and the filtrate evaporated. The crude product was triturated with water, filtered and dried in vacuo to to give the subtitled product as a cream solid (9.3g).
  • step (e) (0.30g) and diethyloxalate were heated at 160°C for 30 mins. The mixture was concentrated in vacuo . Purification by flash chromatography over silica using dichloromethane/methanol (9:1) as eluant afforded the title compound (0.045g). m.p. 243-246°C MS: APCI 396 (M+H, 100%) 1 H NMR: ⁇ (DMSO) 1.12 (d, 3H), 3.43 (m, 2H), 4.14 (m, 1H), 4.38 (q, 2H), 6.79 (d, 1H), 7.13 (m, 1H), 7.30 (m, 1H), 7.45 (t, 1H).
  • step (e) 190 mg
  • ethanol (30 ml) was added iminomethoxy-acetic acid, methyl ester hydrochloride (85mg) ( J. Chem. Soc., Perkin 1, 1999, 1783-93 ) followed by N,N -diisopropylethylamine (70ul) and the mixture heated under reflux for 24 hours.
  • the mixture was evaporated to dryness and purified by silica chromatography (ethyl acetate) to give the title compound (55mg).
  • step (f) The product of Example 1, step (f) (250mg), 1-methyl-1H imidazole-2-thiol (375mg) and butyllithium (0.6ml, 2.5M solution in hexanes) were dissolved in N-methylpyrrolidinone (10ml) and the mixture heated to 100°C for 2 hours. The cooled reaction mixture was diluted with ethyl acetate and washed 4x with saturated aqueous ammonium chloride. The organic phase was dried over magnesium sulphate, filtered and evaporated. The crude product was purified by silica chromatography (20:1 dichloromethane:methanol) to give the title compound (95mg). m.p.
  • step (f) 250mg was dissolved in methanol (10ml) and butyllithium (0.6ml, 2.5M solution in hexanes) was added. The mixture was heated at reflux for 48 hours. The cooled reaction mixture was evaporated and purified by silica chromatography (20:1 dichloromethane:methanol) followed by recrystallisation from methanol to give the title compound (15mg).
  • Examples 8 to 36 were prepared by the method of Example 1 step (g) by reaction of the product of Example 1, step (f) with the appropriate amine or thiol.
  • the product purified by either (a) column chromatography on silica gel, eluting with 10% methanol in dichloromethane, followed by trituration with methanol or (b) reverse phase chromatography using a Waters Xterra column with acetonitrile and 0.2% 0.880 NH 4 OH solution as buffer to give the products as a solid as shown in table 1.
  • [ 125 I]IL-8 (human, recombinant) was purchased from Amersham, U.K. with a specific activity of 2,000Ci/mmol. All other chemicals were of analytical grade. High levels of hrCXCR2 were expressed in HEK 293 cells (human embryo kidney 293 cells ECACC No. 85120602) ( Lee et al. (1992) J. Biol. Chem. 267 pp16283-16291 ). hrCXCR2 cDNA was amplified and cloned from human neutrophil mRNA. The DNA was cloned into PCRScript (Stratagene) and clones were identified using DNA.
  • the coding sequence was sub-cloned into the eukaryotic expression vector RcCMV (Invitrogen). Plasmid DNA was prepared using Quiagen Megaprep 2500 and transfected into HEK 293 cells using Lipofectamine reagent (Gibco BRL). Cells of the highest expressing clone were harvested in phosphate-buffered saline containing 0.2%(w/v) ethylenediaminetetraacetic acid (EDTA) and centrifuged (200g, 5min.).
  • EDTA ethylenediaminetetraacetic acid
  • the cell pellet was resuspended in ice cold homogenisation buffer [10mM HEPES (pH 7.4),1mM dithiothreitol, 1mM EDTA and a panel of protease inhibitors (1mM phenyl methyl sulphonyl fluoride, 2 ⁇ g/ml soybean trypsin inhibitor, 3mM benzamidine, 0.5 ⁇ g/ml leupeptin and 100 ⁇ g/ml bacitracin)] and the cells left to swell for 10 minutes.
  • the cell preparation was disrupted using a hand held glass mortar/PTFE pestle homogeniser and cell membranes harvested by centrifugation (45 minutes,100,000g, 4°C).
  • the membrane preparation was stored at -70°C in homogenisation buffer supplemented with Tyrode's salt solution (137mM NaCl, 2.7mM KCl, 0.4mM NaH 2 PO 4 ), 0.1%(w/v) gelatin and 10%(v/v) glycerol.
  • the assay was initiated with the addition of membranes and after 1.5 hours at room temperature the membranes were harvested by filtration using a Millipore MultiScreen vacuum manifold and washed twice with assay buffer (without bacitracin). The backing plate was removed from the MultiScreen plate assembly, the filters dried at room temperature, punched out and then counted on a Cobra ⁇ -counter.
  • Human neutrophils were prepared from EDTA-treated peripheral blood, as previously described ( Baly et al. (1997) Methods in Enzymology 287 pp70-72 ), in storage buffer [Tyrode's salt solution (137mM NaCl, 2.7mM KCl, 0.4mM NaH 2 PO 4 ) supplemented with 5.7mM glucose and 10mM HEPES (pH 7.4)].
  • the chemokine GRO ⁇ (human, recombinant) was purchased from R&D Systems (Abingdon, U.K.). All other chemicals were of analytical grade. Changes in intracellular free calcium were measured fluorometrically by loading neutrophils with the calcium sensitive fluorescent dye, fluo-3, as described previously ( Merritt et al. (1990) Biochem. J. 269, pp513-519 ).
  • FLIPR Fluorometric Imaging Plate Reader

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Diabetes (AREA)
  • Cardiology (AREA)
  • Endocrinology (AREA)
  • Dermatology (AREA)
  • Urology & Nephrology (AREA)
  • Immunology (AREA)
  • Virology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Rheumatology (AREA)
  • Hematology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pain & Pain Management (AREA)
  • Molecular Biology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Hospice & Palliative Care (AREA)
  • AIDS & HIV (AREA)
  • Obesity (AREA)
  • Psychiatry (AREA)
  • Emergency Medicine (AREA)
EP02749129A 2001-08-14 2002-08-09 Pteridinone derivatives as modulators of chemokine receptor activity Expired - Lifetime EP1419158B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
SE0102716 2001-08-14
SE0102716A SE0102716D0 (sv) 2001-08-14 2001-08-14 Novel compounds
PCT/GB2002/003684 WO2003024966A1 (en) 2001-08-14 2002-08-09 Pteridinone derivatives as modulators of chemokine receptor activity

Publications (2)

Publication Number Publication Date
EP1419158A1 EP1419158A1 (en) 2004-05-19
EP1419158B1 true EP1419158B1 (en) 2007-08-01

Family

ID=20285026

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02749129A Expired - Lifetime EP1419158B1 (en) 2001-08-14 2002-08-09 Pteridinone derivatives as modulators of chemokine receptor activity

Country Status (8)

Country Link
US (2) US20050010047A1 (enrdf_load_stackoverflow)
EP (1) EP1419158B1 (enrdf_load_stackoverflow)
JP (1) JP2005507390A (enrdf_load_stackoverflow)
AT (1) ATE368664T1 (enrdf_load_stackoverflow)
DE (1) DE60221537T2 (enrdf_load_stackoverflow)
ES (1) ES2289124T3 (enrdf_load_stackoverflow)
SE (1) SE0102716D0 (enrdf_load_stackoverflow)
WO (1) WO2003024966A1 (enrdf_load_stackoverflow)

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE9903544D0 (sv) 1999-10-01 1999-10-01 Astra Pharma Prod Novel compounds
GB2359081A (en) 2000-02-11 2001-08-15 Astrazeneca Uk Ltd Pharmaceutically active thiazolopyrimidines
GB2359078A (en) 2000-02-11 2001-08-15 Astrazeneca Uk Ltd Pharmaceutically active pyrimidine derivatives
GB2359551A (en) 2000-02-23 2001-08-29 Astrazeneca Uk Ltd Pharmaceutically active pyrimidine derivatives
SE0003828D0 (sv) 2000-10-20 2000-10-20 Astrazeneca Ab Novel compounds
SE0101322D0 (sv) 2001-04-12 2001-04-12 Astrazeneca Ab Novel compounds
GB0221829D0 (en) * 2002-09-20 2002-10-30 Astrazeneca Ab Novel compound
GB0221828D0 (en) 2002-09-20 2002-10-30 Astrazeneca Ab Novel compound
EP1520586A1 (en) * 2003-09-30 2005-04-06 Institut National De La Sante Et De La Recherche Medicale (Inserm) Inhibition of fractalkine or of its receptor for the treatment of atopic allergic diseases
GB0328243D0 (en) 2003-12-05 2004-01-07 Astrazeneca Ab Methods
EP1915155A1 (en) * 2005-08-03 2008-04-30 Boehringer Ingelheim International GmbH Dihydropteridinones in the treatment of respiratory diseases
WO2009022185A2 (en) * 2007-08-16 2009-02-19 Astrazeneca Ab 6, 6-fused heterocycles, their pharmaceutical compositions and methos of use
EP2961755B1 (de) * 2013-03-01 2017-10-18 Bayer Pharma Aktiengesellschaft Trifluormethyl-substituierte annellierte pyrimidine und ihre verwendung
CN105026405B (zh) * 2013-03-01 2017-08-08 拜耳制药股份公司 苄基‑取代的吡唑并吡啶及其用途
JP6463366B2 (ja) 2013-10-10 2019-01-30 イースタン バージニア メディカル スクール １２−リポキシゲナーゼ阻害物質としての４−（（２−ヒドロキシ−３−メトキシベンジル）アミノ）ベンゼンスルホンアミド誘導体
HUE045847T2 (hu) * 2014-04-14 2020-01-28 Boehringer Ingelheim Int Vegyületek, mint ror-gamma modulátorok
CN110540525B (zh) * 2019-09-19 2022-11-22 广西师范大学 一种3-硫醚基喹喔啉酮化合物的合成方法

Family Cites Families (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2924472A (en) * 1957-06-27 1960-02-09 Gen Motors Corp Pipe joint seal
US3318900A (en) * 1964-05-06 1967-05-09 Janssen Pharmaceutica Nv Derivatives of benzimidazolinyl piperidine
BE668603A (enrdf_load_stackoverflow) * 1964-08-20
US4120521A (en) * 1975-08-28 1978-10-17 Rieber & Son Plastic-Industri A/S Combined mould element and sealing ring
EG12406A (en) * 1976-08-12 1979-03-31 Janssen Pharmaceutica Nv Process for preparing of novel n-aryl-n-(1-l-4-piperidinyl)-arylacetamides
GB1600293A (en) * 1977-02-04 1981-10-14 British Oceanics Ltd Sealing arrangements
US4188040A (en) * 1977-04-06 1980-02-12 Firma WOCO Franz-Josef Wolf & Co. Sealing ring
DE2726959A1 (de) * 1977-06-15 1979-01-18 Arlt Christian Dichteinsatz zum dichten verbinden von zwei rohren
FR2421899A1 (fr) * 1978-01-16 1979-11-02 Roussel Uclaf Nouveaux derives du tetrahydropyridinyl-indole et leurs sels, le procede de preparation et l'application a titre de medicaments de ces nouveaux produits
US4410528A (en) * 1980-05-16 1983-10-18 Kyowa Hakko Kogyo Co., Ltd. Hypotensive piperidine derivatives
DE3219522A1 (de) * 1981-10-28 1983-12-01 Denso-Chemie Wedekind Kg, 5090 Leverkusen Steckmuffendichtung fuer rohre
FR2547888B1 (fr) * 1983-06-22 1985-12-13 Sabla Sa Bague d'etancheite a implants pour tuyaux a emboitement
SE8800348L (sv) * 1988-02-03 1989-08-04 Forsheda Ab Taetningsring och verktyg foer framstaellning daerav
US5169161A (en) * 1991-09-19 1992-12-08 Hail Mary Rubber Co., Inc. Symmetrical gasket for pipe joints
DE4134089C2 (de) * 1991-10-15 1994-10-13 Dueker Eisenwerk Schubgesicherte Muffenverbindung
DE4229609C2 (de) * 1992-09-04 2003-05-08 Forsheda Stefa Gmbh Abdichtung zwischen zwei ineinandersteckbaren Teilen
US5521197A (en) * 1994-12-01 1996-05-28 Eli Lilly And Company 3-<1-alkylenearyl>-4-<1,2,3,6-tetrahydropyridinyl>-and 3-<1-alkylenearyl>-4-piperidinyl-1h-indoles: new 5-HT1F agonists
SE515033C2 (sv) * 1995-12-27 2001-06-05 Forsheda Ab Tätningsanordning
EP1035123B1 (en) * 1997-11-28 2003-08-20 Sumitomo Pharmaceuticals Company, Limited Novel heterocyclic compounds
AU747508B2 (en) * 1998-03-19 2002-05-16 Nihon Nohyaku Co., Ltd. Arylpiperidine derivatives and use thereof
MA26659A1 (fr) * 1998-08-06 2004-12-20 Pfizer Dérivés de benzimidazole nouveaux, compositions pharmaceutiques les contenant et procédé pour leur préparation.
SE9802729D0 (sv) * 1998-08-13 1998-08-13 Astra Pharma Prod Novel Compounds
US5988695A (en) * 1998-08-26 1999-11-23 S&B Technical Products, Inc. Pipe gasket with embedded ring
US6248755B1 (en) * 1999-04-06 2001-06-19 Merck & Co., Inc. Pyrrolidine modulators of chemokine receptor activity
US6142484A (en) * 1999-04-15 2000-11-07 Vassallo Research & Development Corporation Composite multi-pressure gasket
WO2000076514A1 (en) * 1999-06-11 2000-12-21 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
CZ2002846A3 (cs) * 1999-09-15 2003-02-12 Warner-Lambert Company Pteridinony, jako inhibitory kinasy
SE9903544D0 (sv) * 1999-10-01 1999-10-01 Astra Pharma Prod Novel compounds
GB2359081A (en) * 2000-02-11 2001-08-15 Astrazeneca Uk Ltd Pharmaceutically active thiazolopyrimidines
WO2001058906A1 (en) * 2000-02-11 2001-08-16 Astrazeneca Ab Pyrimidine compounds and their use as modulators of chemokine receptor activity
GB2359078A (en) * 2000-02-11 2001-08-15 Astrazeneca Uk Ltd Pharmaceutically active pyrimidine derivatives
GB2359551A (en) * 2000-02-23 2001-08-29 Astrazeneca Uk Ltd Pharmaceutically active pyrimidine derivatives
GB0005642D0 (en) * 2000-03-10 2000-05-03 Astrazeneca Uk Ltd Chemical compounds
AU2001242744B2 (en) * 2000-03-24 2005-07-21 Meiji Seika Kaisha Ltd Diphenylalkylamine derivatives useful as opioid delta receptor ligands
SE0003828D0 (sv) * 2000-10-20 2000-10-20 Astrazeneca Ab Novel compounds
SE0004110L (sv) * 2000-11-10 2002-05-11 Forsheda Ab Tätningsring
SE0101322D0 (sv) * 2001-04-12 2001-04-12 Astrazeneca Ab Novel compounds
GB0221829D0 (en) * 2002-09-20 2002-10-30 Astrazeneca Ab Novel compound
GB0221828D0 (en) * 2002-09-20 2002-10-30 Astrazeneca Ab Novel compound
GB0328243D0 (en) * 2003-12-05 2004-01-07 Astrazeneca Ab Methods

Also Published As

Publication number Publication date
EP1419158A1 (en) 2004-05-19
US20070142352A1 (en) 2007-06-21
SE0102716D0 (sv) 2001-08-14
US20050010047A1 (en) 2005-01-13
DE60221537T2 (de) 2008-04-24
ATE368664T1 (de) 2007-08-15
WO2003024966A1 (en) 2003-03-27
ES2289124T3 (es) 2008-02-01
JP2005507390A (ja) 2005-03-17
DE60221537D1 (de) 2007-09-13

Similar Documents

Publication Publication Date Title
US20070142352A1 (en) Pteridinone Derivatives as Modulators of Chemokine Receptor Activity
US7579342B2 (en) Pteridine compounds for the treatment of psoriasis
US6806273B1 (en) Compounds
EP1328319B1 (en) 7-amino-2-alkylthiopteridin-4-yl-amines for the treatment of chemokine-related diseases
EP1257555B1 (en) Pyrimidine compounds and their use as modulators of chemokine receptor activity
IL150952A (en) Preparation of dosage forms of clear aqueous solution with bile acids
ZA200202380B (en) Novel thiazolo(4,5-D)pyrimidine compounds.
US6958344B2 (en) Pyrimidine compounds and their use as modulators of chemokine receptor activity
EP1385854B1 (en) Thiazolopyrimidines and their use as modulators of chemokine receptor activity
EP1257556B1 (en) Thiazolopyrimidines and their use as modulators of chemokine receptor activity
GB2359079A (en) Pharmaceutically active pyrimidine derivatives
HK1050899B (en) Pteridine compounds for the treatment of psoriasis

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20040315

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LI LU MC NL PT SE SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

RIN1 Information on inventor provided before grant (corrected)

Inventor name: HUNT, SIMON, FRAZER

Inventor name: BONNERT, ROGER, VICTOR

Inventor name: CAGE, PETER, ALAN

Inventor name: AUSTIN, RUPERT, PHILIPASTRAZENECA R&D CHAMWOOD

Inventor name: WALTERS, IAIN, ALASTAIR, STEWART

17Q First examination report despatched

Effective date: 20040615

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LI LU MC NL PT SE SK TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REF Corresponds to:

Ref document number: 60221537

Country of ref document: DE

Date of ref document: 20070913

Kind code of ref document: P

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

ET Fr: translation filed
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20070801

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20071101

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20070801

NLV1 Nl: lapsed or annulled due to failure to fulfill the requirements of art. 29p and 29m of the patents act
REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2289124

Country of ref document: ES

Kind code of ref document: T3

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20070801

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20070801

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20071102

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20070831

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20070801

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20070801

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20070801

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080102

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20080506

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20070809

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20080708

Year of fee payment: 7

Ref country code: DE

Payment date: 20080829

Year of fee payment: 7

Ref country code: ES

Payment date: 20080808

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20080807

Year of fee payment: 7

Ref country code: IT

Payment date: 20080818

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20080708

Year of fee payment: 7

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20070801

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 20080808

Year of fee payment: 7

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20070801

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20070809

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20070801

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20090809

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090831

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090831

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20100430

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100302

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090831

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20090810

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090809

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090809

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090810

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090810